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Metalloproteinases regulate CD40L shedding from platelets and pulmonary recruitment of neutrophils in abdominal sepsis

Rahman, Milladur LU ; Roller, Jonas LU ; Zhang, Su LU ; Syk, Ingvar LU ; Menger, Michael; Jeppsson, Bengt LU and Thorlacius, Henrik LU (2012) In Inflammation Research 61(6). p.571-579
Abstract (Swedish)
Abstract in Undetermined

OBJECTIVE: Platelets promote sepsis-induced activation of neutrophils via secretion of CD40L. However, the mechanism regulating the release of platelet-derived CD40L is not known. We hypothesized that matrix metalloproteinases (MMPs) might regulate shedding of platelet-expressed CD40L and neutrophil activation in sepsis.



METHODS: Wild-type C57BL/6 mice were subjected to cecal ligation and puncture (CLP). Animals were pretreated with a broad-range MMP inhibitor, GM6001, prior to CLP induction. Edema formation, CXC chemokine and myeloperoxidase (MPO) levels and bronchoalveolar neutrophils in the lung as well as plasma levels of CD40L were quantified. Flow cytometry was used to... (More)
Abstract in Undetermined

OBJECTIVE: Platelets promote sepsis-induced activation of neutrophils via secretion of CD40L. However, the mechanism regulating the release of platelet-derived CD40L is not known. We hypothesized that matrix metalloproteinases (MMPs) might regulate shedding of platelet-expressed CD40L and neutrophil activation in sepsis.



METHODS: Wild-type C57BL/6 mice were subjected to cecal ligation and puncture (CLP). Animals were pretreated with a broad-range MMP inhibitor, GM6001, prior to CLP induction. Edema formation, CXC chemokine and myeloperoxidase (MPO) levels and bronchoalveolar neutrophils in the lung as well as plasma levels of CD40L were quantified. Flow cytometry was used to determine expression of Mac-1 on neutrophils and CD40L on platelets. Intravital fluorescence microscopy was used to analyze leukocyte-endothelial cell interactions in the pulmonary microcirculation.



RESULTS: The MMP inhibitor reduced sepsis-induced release of CD40L and maintained normal levels of CD40L on platelets. Inhibition of MMP decreased CLP-induced neutrophil expression of Mac-1, formation of CXC chemokines and edema as well as neutrophil infiltration in the lung. Intravital fluorescence microscopy revealed that the MMP inhibitor attenuated leukocyte adhesion in venules whereas capillary trapping of leukocytes was not affected by MMP inhibition.



CONCLUSIONS: We describe a novel role of metalloproteinases in regulating platelet-dependent activation and infiltration of neutrophils in septic lung injury which might be related to controlling CD40L shedding from platelets. We conclude that targeting metalloproteinases may be a useful strategy for limiting acute lung injury in abdominal sepsis. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Adhesion, Neutrophils, Chemokines, Lung injury, Sepsis
in
Inflammation Research
volume
61
issue
6
pages
571 - 579
publisher
Birkhaüser
external identifiers
  • pmid:22349180
  • wos:000303820100006
  • scopus:84865152135
ISSN
1420-908X
DOI
10.1007/s00011-012-0446-6
language
English
LU publication?
yes
id
65e4ff9e-b0c6-4a5e-997c-8abad0103626 (old id 2365001)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22349180?dopt=Abstract
date added to LUP
2012-03-02 14:19:15
date last changed
2017-08-27 03:43:38
@article{65e4ff9e-b0c6-4a5e-997c-8abad0103626,
  abstract     = {<b>Abstract in Undetermined</b><br/><br>
OBJECTIVE: Platelets promote sepsis-induced activation of neutrophils via secretion of CD40L. However, the mechanism regulating the release of platelet-derived CD40L is not known. We hypothesized that matrix metalloproteinases (MMPs) might regulate shedding of platelet-expressed CD40L and neutrophil activation in sepsis.<br/><br>
<br/><br>
METHODS: Wild-type C57BL/6 mice were subjected to cecal ligation and puncture (CLP). Animals were pretreated with a broad-range MMP inhibitor, GM6001, prior to CLP induction. Edema formation, CXC chemokine and myeloperoxidase (MPO) levels and bronchoalveolar neutrophils in the lung as well as plasma levels of CD40L were quantified. Flow cytometry was used to determine expression of Mac-1 on neutrophils and CD40L on platelets. Intravital fluorescence microscopy was used to analyze leukocyte-endothelial cell interactions in the pulmonary microcirculation.<br/><br>
<br/><br>
RESULTS: The MMP inhibitor reduced sepsis-induced release of CD40L and maintained normal levels of CD40L on platelets. Inhibition of MMP decreased CLP-induced neutrophil expression of Mac-1, formation of CXC chemokines and edema as well as neutrophil infiltration in the lung. Intravital fluorescence microscopy revealed that the MMP inhibitor attenuated leukocyte adhesion in venules whereas capillary trapping of leukocytes was not affected by MMP inhibition.<br/><br>
<br/><br>
CONCLUSIONS: We describe a novel role of metalloproteinases in regulating platelet-dependent activation and infiltration of neutrophils in septic lung injury which might be related to controlling CD40L shedding from platelets. We conclude that targeting metalloproteinases may be a useful strategy for limiting acute lung injury in abdominal sepsis.},
  author       = {Rahman, Milladur and Roller, Jonas and Zhang, Su and Syk, Ingvar and Menger, Michael and Jeppsson, Bengt and Thorlacius, Henrik},
  issn         = {1420-908X},
  keyword      = {Adhesion,Neutrophils,Chemokines,Lung injury,Sepsis},
  language     = {eng},
  number       = {6},
  pages        = {571--579},
  publisher    = {Birkhaüser},
  series       = {Inflammation Research},
  title        = {Metalloproteinases regulate CD40L shedding from platelets and pulmonary recruitment of neutrophils in abdominal sepsis},
  url          = {http://dx.doi.org/10.1007/s00011-012-0446-6},
  volume       = {61},
  year         = {2012},
}